Monday, March 25, 2013

Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

Øystein Flugemail,

Ove Bruland,

Kristin Risa,

Anette Storstein,

Einar K. Kristoffersen,

Dipak Sapkota,

Halvor Næss,

Olav Dahl,

Harald Nyland,

Olav Mella

Abstract

Background

Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and Findings

In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.

The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

Conclusion

The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

Funding:The work received financial support from Helse Vest grant no 911557, and also from the legacy of Torstein Hereid. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests:Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome. Family members of WO2009083602 A1 are pending, as well as granted US 12/348024. The two authors ØF and OM are named as inventors in these applications. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Saturday, March 23, 2013

Dr. Maria Gjerpe, an ME patient for 30 years, explains how and why MEandYou are going to crowdfund a Rituximab study:
Within 90 days we are going to raise 7 million Norwegian krone ($1.2 million) to fund a study on 140 ME/CFS patients at Haukeland Hospital in Bergen, Norway.
Will we – the patients, relatives, friends – be the first in the world to crowdfund a clinical trial?
And can we engage both sides of the Atlantic to make it happen?
Yes!
In 2011, a study at Haukeland Hospital on the use of the immunosuppressive medication Rituximab against ME attracted international attention. Two-thirds of the patients in the study experienced significant improvement after being treated with the drug.
Read more>>
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Abstract (provisional)

Background

Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability.

Methods

Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups.

Conclusions

Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.

The complete article is available as aprovisional PDF. The fully formatted PDF and HTML versions are in production.

Thursday, March 21, 2013

WASHINGTON — Researchers say they have found physical proof that Gulf War illness is caused by damage to the brain — and that proof may ultimately help civilians who suffer from chronic fatigue syndrome and fibromyalgia.

Using fMRI machines, the Georgetown University researchers were able to see anomalies in the bundle of nerve fibers that interpret pain signals in the brain in 31 Gulf War veterans. The research will be published Wednesday inPLOS ONEjournal.

The findings are "huge," because an fMRI allows doctors to diagnose a person with Gulf War illness quickly, said James Baraniuk, senior author and professor of medicine at Georgetown University Medical Center. The research, he said, also shows that Gulf War illness is not psychological.

An fMRI, or "functional" MRI, is a scan that measures activity by detecting how blood flows through the brain.

Many veterans have had difficulties getting benefits and treatment for a service-connected condition because doctors assumed they were either faking it or suffering from post-traumatic stress. "That's a problem with all physicians — VA, military or civilian," Baraniuk said. "If it doesn't fall within their small world of known diseases, then the patient is nuts."

Gulf War illness is a series of symptoms that has affected more than 250,000 veterans of the 1991 war against Iraq in response to Iraq's invasion of Kuwait.

Baraniuk said the correlation of anomalies in the brain's white matter with Gulf War illness has not been studied before. Researchers, he said, also found that fatigue and pain worsen congruently in the veterans.

This new condition suggested in the bible of mental health diagnoses lacks specificity, saysAllen Frances

The fuzzy boundary between psychiatry and general medicine is about to experience a seismic shift. The next edition of the American Psychiatric Association’sDiagnostic and Statistical Manual of Mental Disorders(DSM) is scheduled for release this May amid controversy about many of its new disorders. Among these, DSM-5 introduces a poorly tested diagnosis—somatic symptom disorder—which risks mislabeling a sizeable proportion of the population as mentally ill.

The relation between psychiatry and the rest of medicine has been difficult to manage both for mental health practitioners and for primary care doctors, and this is even more problematic for patients caught in-between. The boundary has never been clear cut or static but has shifted back and forth depending on new findings and fashions. The realm of psychiatry would shrink, and that of medicine would expand, whenever advancing science discovered a cause for a previously poorly understood presentation. The classic example of this is “general paresis of the insane,” which went from psychiatry to neurology as soon as the spirochete was identified as the causal agent.

In DSM-5, “somatic symptom disorder” appears in a new section, “Somatic symptoms and related disorders,” which replaces the “Somatoform disorders” section found in DSM-IV. This new category will extend the scope of mental disorder classification by eliminating the requirement that somatic symptoms must be “medically unexplained.” In DSM-5, the focus shifts to “excessive” responses to distressing, chronic, somatic symptoms with associated “dysfunctional thoughts, feelings, or behaviors.”

The overinclusiveness of this diagnosis is suggested by the results of the DSM-5 field trial study reported by the somatic symptom disorder work group at the 2012 annual meeting of the American Psychiatric Association. Somatic symptom disorder captured 15% of patients with cancer or heart disease and 26% with irritable bowel syndrome or fibromyalgia, and it had a high false positive rate of 7% among healthy people in the general population.1The rate of psychiatric disorder among medically ill patients is unknown, but these rates seem high, and the burden of proof before introducing any new diagnosis is that it has a favourable risk to benefit ratio. Yet the proposed diagnosis is unsupported by any substantial evidence on its likely validity and safety and was strongly opposed by patients, families, caregivers, and advocacy organizations.2

The DSM-5 definition of somatic symptom disorder is loose. It requires only one bodily symptom that is distressing or disruptive to daily life, which lasts at least six months. It also requires one of the following psychological or behavioral responses: disproportionate thoughts about the seriousness of symptom(s); persistently high level of anxiety about symptom(s); or excessive time and energy spent on health concerns.3This is far looser than the (rarely used) definition of somatization disorder in DSM-IV. This required a history of many medically unexplained symptoms before the age of 30 years that occurred over several years and which resulted in treatment being sought or psychosocial impairment. A total of eight or more medically unexplained symptoms were needed from four specified symptom groups, with at least four pain and two gastrointestinal symptoms.4
Previous DSM criteria have always included reminders to clinicians to rule out other explanations before concluding that any mental disorder is present. I suggested to the working group that similar reminders should be included this time and that before somatic symptom disorder is diagnosed clinicians should consider whether the health concerns are completely unrealistic or whether an underlying medical disorder might account for them. I also suggested that clinicians should consider whether symptoms might be caused by one of several mental disorders that often present with physical problems (such as depression, generalized anxiety, or panic disorder).

The DSM-5 working group reviewed these suggestions and rejected them.

Misapplication of these catch-all criteria, especially in harried primary care practice, may result in inappropriate diagnoses of mental disorder and inappropriate medical decision making.5Millions of people could be mislabeled, with the burden falling disproportionately on women, because they are more likely to be casually dismissed as “catastrophizers” when presenting with physical symptoms.

A false positive diagnosis of somatic symptom disorder harms patients because it may result in any underlying medical causes being missed. It also subjects patients to stigma, inappropriate drugs, psychotherapy, and iatrogenic disease; disadvantages them in decisions relating to employment, education, and healthcare entitlements; skews their self perceptions and those of family and friends; and places parents of children with chronic illness at risk of accusation of “overinvolvement” or of maintaining “sick role behavior.”

Every diagnostic decision is a delicate balancing act between definitions that will result in too much versus too little diagnosis—the DSM-5 work group chose a remarkably sensitive definition that is also remarkably non-specific. This reflected a consistent bias throughout DSM-5 to expand the boundaries of psychiatric diagnosis with what I believe was insufficient attention to the risks of the ensuing false positive mislabeling.

The DSM-5 diagnosis of somatic symptom disorder is based on subjective and difficult to measure cognitions that will enable a “bolt-on” diagnosis of mental disorder to be applied to all medical conditions, irrespective of cause. ICD-11 (International Classification of Diseases, 11th revision) is now being prepared by some of the same people who worked on DSM-5.67Unless ICD-11 applies a higher standard of evidence and risk benefit analysis, it may repeat the mistake of casually mislabeling the physically ill as also mentally disordered.8

The late Thomas Szasz once said: “In the days of the Malleus, if the physician could find no evidence of natural illness, he was expected to find evidence of witchcraft: today, if he cannot diagnose organic illness, he is expected to diagnose mental illness.”9Szasz’s general critique of psychiatry was too broad, but he was correct when it comes to the loosely defined somatic symptom disorder in DSM-5. Clinicians are best advised to ignore this new category. When a psychiatric diagnosis is needed for someone who is overly worried about medical problems the more benign and accurate diagnosis is adjustment disorder.

Notes

Cite this as:BMJ2013;346:f1580

Footnotes

Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I will publish two books that include references to DSM-5 (Saving NormalandEssentials of Psychiatric Diagnosis) and I chaired the DSM-IV task force.

"Plenty of people are still dying of diseases which other people do not believe." (Dr. M.N.C. Dukes).CBT and GET for ME: "There is no nonsense so gross that society will not, at some time, make a doctrine of it and defend it with every weapon of communal stupidity."

Robertson Davies

THE NICEGUIDELINES BLOG VERSUS THE NICEGUIDELINES

These are NOT the NICEGuidelines. This is "The NICEGUIDELINES BLOG." What are the differences:

The NICE Guidelines are biased publications based on the GOBSART (Good Old Boys Sitting Around a Table) approach.

This Blog however is not only evidence based but also uses critical reading to judge papers and articles. I also use common sense and listen to others. And finally I read both psychiatric and medical evidence and opinions from around the world to come to a conclusion.

I’m not sponsored by anybody or paid by whatever company as seems to be the norm with many psycho people who publish the same article almost on a weekly base.

So if you value an opinion, formed as a result of participating in many ME activities, for example being bed bound for years, you have come to the right BLOG. All these activities have allowed me to form an opinion as a Doctor and as a Patient. And that is important as the voice of the latter is discarded by many including NICE.

If you don’t read this blog, you will miss out on “accredited” medical education. If you do read it, you may actually become a doctor who doesn’t stop thinking or forgets to ask critical questions. Many good things, including satisfied patients are at your command.

So, if you arrived here for the straightforward GOBSART approach, I will disappoint you. If you are interested in forming your own opinion about ME, and other interesting things, read on!

About Dr. Speedy.

I am a Family Physician or GP as it is called in Australia or the UK. I am also an ME patient unfortunately. Bedbound that is. So at the moment I’m in private practice so to speak. I’ve got only one patient, ME, or is it me?

I graduated as a doctor a long time ago, and I am the founder and editor of The NICEGUIDELINES BLOG, an internet based ME BLOG that is devoted to critical reading and cheering you or ME up.

I have the following conflict of interest: I would like to get better and see that the wasting of public money on CBT (talk therapy for a neurological disease, really helpful) and other silly therapies for ME stops, and will be used in better ways.

My goal has always been to help, and if possible, cure patients. With this disease you will soon find out that many psychiatrists and psychologists are only in it to make money and get their name in the spotlight. And what happens to and with the patients is irrelevant.

I stand to benefit both mentally, physically and also financially if this silliness would stop, and I would get my health back, and I can go back to work and have a normal life again. Please evaluate my postings with this in mind! And remember, there are also (lots of) psychiatrists and psychologists who haven’t switched their brain off.